Researchers at Johns Hopkins have discovered that
blood vessels in the head can guide growing
facial nerve cells with blood pressure-controlling
proteins. The findings, which suggest that blood
vessels throughout the body might have the same power of
persuasion over many nerves, are published
in the April 10 issue of Nature.

"We're excited to have stumbled across another family
of proteins that can tell a growing nerve
which way to grow," said David Ginty, a professor of
neuroscience in the School of Medicine and a
Howard Hughes Medical Institute investigator. "But the
really interesting thing is that the nerves
appear to use blood vessels as guideposts to direct their
growth in one of several possible directions."

The research team studied in mice a group of about
15,000 nerve cells known as the superior
cervical ganglia, or SCG, which extend projections that
innervate various structures in the head
including the eyes, mouth and salivary glands. The SCG sit
in a Y-like branching point of the blood
vessel in the neck that supplies the head with blood, the
carotid artery. In the developing embryo,
nerve projections grow out of the SCG and grow along one of
the two branches of the carotid artery;
the nerves that grow along the internal carotid innervate
the eyes and mouth among other head
structures, and those that grow along the external carotid
innervate the salivary glands.

To figure out how nerve cells "choose" to grow along
the external carotid artery to innervate
the salivary glands, the team looked for genes that appear
to be preferentially turned on in the
external carotid and off in the internal carotid. "There
are only two directions they can go," Ginty
said, "and we wanted to know if they choose their direction
or if the decision to go one way or the
other is random."

The researchers found one gene that is expressed
preferentially in the external carotid, a gene
that makes the blood pressure-regulating protein,
endothelin, active. "It comes as no surprise that
something critical for regulating the cardiovascular system
in the adult also is used for directing
nerve growth in the developing embryo," Ginty said. "The
genome is limited, and nature has figured out
a way to use things over and over again for unrelated
functions."

Further examination of the arteries in mouse embryos
confirmed that endothelin is found only
in the external carotid. To confirm that the nerve cell
projections grow toward endothelin, the
researchers removed SCGs and grew each one next to an
endothelin-soaked bead. Checking on them
three days later, the team found that nerves from the SCGs
had grown toward the beads. To be
certain that endothelin directs nerve growth in the living
animal, the researchers then looked in mice
that had the endothelin gene removed. Sure enough, these
mice had no nerves growing along their
external carotid arteries.

The team then wondered if all growing nerves in the
SCG can respond to endothelin. So they
looked for the endothelin receptors in SCG nerves and found
that only a subset of SCG nerves make
endothelin receptors, and concluded that those nerves
somehow already had been chosen to respond
to the endothelin made by the external carotid.

"How do these nerve cells know which target organ
they're supposed to innervate when they all
come from the same progenitor?" Ginty asked. "This is what
we're going to study next."

The research was funded by the National Institutes of
Health and the Howard Hughes Medical
Institute.

Authors on the paper are Takako Makita and Ginty, both
of Johns Hopkins; Henry Sucov, of the
University of Southern California; Cheryl Gariepy, of the
University of Michigan; and Masashi
Yanagisawa, of the University of Texas Southwestern Medical
Center.